The present invention relates to a combination of substances and to the use thereof for treating a tumor by induction of a tumor senescence.
In spite of many different approaches in the last decades, a successful tumor prevention and therapy is still a big challenge in science and medicine. Usually, nowadays, tumor therapies are performed by a surgical removal of the tumor, by means of irradiation, in which case normally ionizing radiation is used, and/or of a chemotherapy. The therapies are also combined. Latest therapies are based on the interaction of drugs with signaling cascades that help the tumors to undergo a pathological proliferation. It is important that all therapies developed up to now usually work only during the therapy application. Various data suggest that none of the therapies available up to now is able to fully eradicate tumors. For this reason, tumors tend to relapse, presumably starting from tumor stem cells (Ref. Nature 2012).
Further, cancer immunotherapies have been developed, in the context of which the respective patient is inoculated with surface antigens being specific for the tumor, with the aim to initiate immune responses, i.e. to kill the tumor cells through cytotoxic CD8 T lymphocytes, also called ‘killer cells’. In still other therapy approaches, immune modulators are used, by means of which the patient's immune system is stimulated such that endogenous defense mechanisms are restored/activated such that they can destroy/kill the tumor. In these therapies, by the activation of endogenous or—in the case of the allergenic bone marrow transplantation—exogenous immune response, the malignant tumor cells destroyed; in most cases, a non-specific activation of the immune system occurs, or the transfer of tumor-specific cytotoxic lymphocytes occurs. Natural killer cells are also used. It applies for these applications, too, that many of the therapies work only during the therapy application, since in the rarest cases they will lead to a complete tumor eradication. Again, the tumors tend to relapse, presumably starting from tumor stem cells.
The role of the immune system during the tumor development has been examined in recent papers: Under certain circumstances, a state of equilibrium can be achieved, so that the development of new tumor cells and the destruction of existing tumor cells will temporarily lead to a standstill of the tumor growth (Koebel et al., Nature 450, 903 (2007); Schreiber et al., Science 331, 1565 (2011)).
Given this background, the efficient control of the tumor stem cells and the efficient inhibition of an exponential growth of the tumor cells by endogenous defense mechanisms is a big challenge for the treating physicians. In spite of the induction of strong, endogenous defense mechanisms that lead to a tumor reduction, in most cases they tend to re-start after completion of the therapy and re-grow after completion of the therapy. Further problems are caused by the drugs, which induce a non-specific immune activation, as their administration is associated with severe side effects. To date, it is assumed that the arrest of the tumor growth by the immune system, provided it occurs, is primarily based on that the immune response accelerates the tumor cell destruction such that an equilibrium between the tumor cell destruction and the natural tumor cell proliferation exists.
Given this background, it is the object of the present invention to provide a novel therapy approach being complementary to the previous therapy approaches oriented toward cytotoxicity, by means of which the development, the formation, and the growth of tumors can efficiently be treated or even prevented. This therapy is based on that the growth and the proliferation of tumor cells—including the tumor stem cells—are arrested in the long term.